J Korean Med Sci.  2021 May;36(18):e133. 10.3346/jkms.2021.36.e133.

Empty Sella Syndrome Associated with Growth Hormone Deficiency: the First Case Report of WeissKruszka Syndrome

• Park J
• Ha DJ
• Seo GH
• Maeng S
• Kang SM
• Kim S
• Lee JE

• KMID: 2515860
• DOI: http://doi.org/10.3346/jkms.2021.36.e133

Abstract

Weiss-Kruszka syndrome (WSKA), caused by heterozygous loss-of-function variants in ZNF462 gene, is a recently described and extremely rare genetic disorder. The main phenotypes include characteristic craniofacial features, ptosis, dysgenesis of the corpus callosum, and neurodevelopmental impairment. We report the first Korean boy with molecularly confirmed WSKA presenting with an atypical manifestation. A 16-year-old boy with a history of bilateral ptosis surgery presented with short stature (−3.49 standard deviation score) and delayed puberty. The patient showed characteristic craniofacial features including an inverted triangular-shaped head, exaggerated Cupid's bow, arched eyebrows, down-slanting palpebral fissures, and poorly expressive face. He had a mild degree of intellectual disability and mild hypotonia. Endocrine studies in the patient demonstrated complete growth hormone deficiency (GHD) associated with empty sella syndrome (ESS), based on a magnetic resonance imaging study for the brain that showed a flattened pituitary gland and cerebrospinal fluid space herniated into the sella turcica. To identify the genetic cause, we performed whole exome sequencing (WES). Through WES, a novel de novo heterozygous nonsense variant, c.4185del; p.(Met1396Ter) in ZNF462 was identified. This is the first case of WSKA accompanied by primary ESS associated with GHD. More clinical and functional studies are needed to elucidate this association.

Keyword

ZNF462; Weiss-Kruszka Syndrome; Empty Sella; Growth Hormone Deficiency

Figure

• 

  Fig. 1 Patient's craniofacial manifestation. (A, B) The patient has arched eyebrows, exaggerated Cupid's bow, and short upturned nose with bulbous nasal tip. (C) Inverted triangular-shaped forehead was shown. (D) Inverted triangular-shaped head shape was shown in back. The figures are published with the consent of the patient and his parents.

• 

  Fig. 2 MRI studies of the brain showing ESS. (A) Sagittal view of brain MRI shows a flattened pituitary gland and CSF space herniated into the sellar turcica. The posterior pituitary gland appears normal. (B) Coronal view of brain MRI shows the pituitary fossa which is largely empty of tissue, replaced by CSF. (C) Axial view of brain MRI shows ESS.MRI = magnetic resonance imaging, ESS = empty sella syndrome, CSF = cerebrospinal fluid.

• 

  Fig. 3 Growth chart of the patient under rhGH replacement therapy. Upper side shows height chart and lower side shows weight chart. The dots indicate the height and weight measurement. The arrow marks the beginning of rhGH treatment start. The patient's height velocity after the start of rhGH was increased 8 cm/year.rhGH = recombinant human growth hormone.

• 

  Fig. 4 Sanger sequencing result of the patient with a novel heterozygous nonsense variant at position 4185 (c.4185del) in ZNF462 gene. The arrow points deletion of ‘c,’ which generates stop codon. The patient's mother did not have the ZNF462 pathogenic variant.

Reference

1. González-Tarancón R, Salvador-Rupérez E, Miramar Gallart MD, Barroso E, Díez García-Prieto I, Pérez Delgado R, et al. A novel mutation in the ZNF462 gene c.3306dup; p.(Gln1103Thrfs*10) is associated to Weiss-Kruszka syndrome. A case report. Acta Clin Belg. 2020; 1–4.

2. Kruszka P. Weiss-Kruszka syndrome. In : Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, editors. GeneReviews^®. Seattle, WA: University of Washington;1993.

3. Nagase T, Nakayama M, Nakajima D, Kikuno R, Ohara O. Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 2001; 8(2):85–95. PMID: 11347906.

4. Weiss K, Wigby K, Fannemel M, Henderson LB, Beck N, Ghali N, et al. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. Eur J Hum Genet. 2017; 25(8):946–951. PMID: 28513610.

5. Uliana V, Percesepe A. Reverse phenotyping comes of age. Mol Genet Metab. 2016; 118(4):230–231. PMID: 27211610.

6. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405–424. PMID: 25741868.

7. Cosemans N, Vandenhove L, Maljaars J, Van Esch H, Devriendt K, Baldwin A, et al. ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder. Eur J Med Genet. 2018; 61(7):376–383. PMID: 29427787.

8. Kruszka P, Hu T, Hong S, Signer R, Cogné B, Isidor B, et al. Phenotype delineation of ZNF462 related syndrome. Am J Med Genet A. 2019; 179(10):2075–2082. PMID: 31361404.

9. Nowick K, Gernat T, Almaas E, Stubbs L. Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain. Proc Natl Acad Sci U S A. 2009; 106(52):22358–22363. PMID: 20007773.

10. De Marinis L, Bonadonna S, Bianchi A, Maira G, Giustina A. Primary empty sella. J Clin Endocrinol Metab. 2005; 90(9):5471–5477. PMID: 15972577.

11. Lee SS, Han AL, Ahn MB, Kim SH, Cho WK, Cho KS, et al. Growth without growth hormone in combined pituitary hormone deficiency caused by pituitary stalk interruption syndrome. Ann Pediatr Endocrinol Metab. 2017; 22(1):55–59. PMID: 28443260.

12. Son HW, Lee JE, Oh SH, Keum C, Chung WY. Effects of long-term growth hormone therapy in a girl with Floating-Harbor syndrome. Ann Pediatr Endocrinol Metab. 2020; 25(2):126–131. PMID: 32615693.

13. Chiloiro S, Giampietro A, Bianchi A, Tartaglione T, Capobianco A, Anile C, et al. Diagnosis of endocrine disease: primary empty sella: a comprehensive review. Eur J Endocrinol. 2017; 177(6):R275–85. PMID: 28780516.

14. Hayakawa K, Konishi Y, Matsuda T, Kuriyama M, Konishi K, Yamashita K, et al. Development and aging of brain midline structures: assessment with MR imaging. Radiology. 1989; 172(1):171–177. PMID: 2740500.

15. Al-Naama N, Mackeh R, Kino T. C₂H₂-type zinc finger proteins in brain development, neurodevelopmental, and other neuropsychiatric disorders: systematic literature-based analysis. Front Neurol. 2020; 11:32. PMID: 32117005.

16. Krishna SS, Majumdar I, Grishin NV. Structural classification of zinc fingers: survey and summary. Nucleic Acids Res. 2003; 31(2):532–550. PMID: 12527760.